This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Subproject #1: Persistent norovirus infection of lymphoid tissue impairs protective immunity Stephanie M. Karst Human noroviruses in the Caliciviridae family are the major cause of nonbacterial gastroenteritis outbreaks worldwide and are emerging pathogens of public health interest. The major goal of this project is to design rationale vaccination strategies to prevent norovirus infection. Human norovirus infection does not induce lasting immunity, potentially a very important observation in terms of rationale vaccine design. We have now recapitulated this atypical pattern of immunity in the mouse model [unreadable]primary MNV-1 infection of mice fails to elicit memory immune responses that protect from mucosal infection or disease. Accumulating evidence by our group and others demonstrates that noroviruses cause persistent infection of lymphoid tissues. We initially hypothesized that persistent viral replication in lymphoid compartments impairs the generation of protective immune responses. However, we have now determined that a second murine norovirus strain, MNV-3, which persistently infects mice for a longer duration than does MNV-1 actually elicits protective immunity. Thus, there does not appear to be a direct correlation between the length of persistent MNV infection and the magnitude of protection afforded by a primary challenge. Interestingly, there is a correlation between protective immunity induction and cell tropism. We therefore hypothesize that MNV infection of mucosal antigen presenting cells impairs the development of protective memory immunity.